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. 2013 May-Jun;5(3):373-83.
doi: 10.4161/mabs.23826. Epub 2013 Mar 25.

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design

Yulia Vugmeyster  1 , Cynthia Rohde  2 , Mylene Perreault  3 , Ruth E Gimeno  4 , Pratap Singh  1
Affiliations

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design

Yulia Vugmeyster et al. MAbs. 2013 May-Jun.

Abstract

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level<10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action.

Keywords: Cachexia; PK/PD modeling; TAM-163; TMDD; TrkB; antibody; body weight; modeling; pharmacodynamics; pharmacokinetics.

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Figures

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Figure 1. Individual and mean (± SD) total body clearance (CL) of TAM-163 in lean cynomolgus and obese rhesus monkeys after a single IV dose determined by non-compartmental analysis (NCA). Monkeys were administered a single IV bolus dose of TAM-163 at indicated dose levels using study designs summarized in Table 1. TAM-163 concentrations in serum samples and total body CL were determined by a specific immunoassay and NCA, respectively, as described in the text. Cyno = cynomolgus monkeys.
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Figure 2. Schematic representation of the TMDD model. Ka and F denote the SC absorption rate and bio-availability, respectively. The Kel, K12 and K21 denote the first order rate constants corresponding to serum elimination, serum to peripheral, and peripheral to serum distribution, respectively. TrkB receptor internalization rate (Kint), baseline levels (R0), and turnover rate (Kdeg) are incorporated into the model along with the association (Kon) and dissociation (Koff) rate constants of TAM-163 binding to TrkB receptor. Ac and Ap denote antibody amount in central and peripheral compartment, respectively.
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Figure 3. TAM-163 serum concentrations in lean cynomolgus monkeys fitted with the TMDD model. The observed data are represented by open circles, whereas model fit is denoted by a solid line. Monkeys were administered a single IV bolus or SC dose of TAM-163 at indicated dose levels using study designs summarized in Table 1. TAM-163 concentrations in serum samples were determined by a specific immunoassay as described in the text. Cyno, cynomolgus monkeys; Conc., concentration.
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Figure 4. TAM-163 serum concentrations in obese rhesus monkeys fitted with the TMDD model. The observed data are represented by open circles, whereas model fit is denoted by a solid line. Monkeys were administered a single IV bolus dose of TAM-163 at indicated dose levels using study designs summarized in Table 1. TAM-163 concentrations in serum samples were determined by a specific immunoassay as described in the text.
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Figure 5. Projection of free target levels, as percentage of total target levels, after a single IV dose of TAM-163 in cynomolgus and rhesus monkeys using the TMDD model. Monkeys were administered a single IV bolus dose of TAM-163 at indicated dose levels using study designs summarized in Table 1. The observed serum concentration and biomesure data were used to estimate % free target at each time point for each dose group, as described in the text. The 28-d (672 h) average free target percentages were calculated to be 62% and 3% for 1 and 20 mg/kg IV doses, respectively. The 28-d time-average target coverage percentages (defined as the inverse of time-average free target percentage) were calculated to be 38% and 97% for 1 and 20 mg/kg IV doses, respectively.
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Figure 6. Projection of target coverage profiles after a single SC dose of TAM-163 administered to humans. (A) Serum TAM-163 concentrations in healthy humans at 0.5, 1, 3, 5 and 15 mg/kg SC doses were projected using the model parameters specified in Table 4. (B) Projected % free target levels at various SC doses in human estimated with the human TMDD model scaled from monkey model parameters. The estimated average free target percentages over 28 d (i.e., 672 h) after single SC doses to humans were 79%, 62%, 23%, 11% and 3% for 0.5, 1, 3, 5 and 15 mg/kg doses, respectively. Conversely, the estimated 28-d time-average % target coverage after single SC doses to humans were 21%, 38%, 77%, 89% and 97% for 0.5, 1, 3, 5 and 15 mg/kg doses, respectively. (C) % Target coverage in humans projected at single SC doses of 0.03, 0.05 and 0.1 mg/kg. Conc., concentration.
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